Bladder over-activity and urinary incontinence are common conditions that present various symptoms that are at best embarrassing and at worst disabling. These conditions are a frequent cause of elderly people's confinement to nursing homes and other protected environments. While they are more common among women than among men, at all ages, these conditions afflict significant numbers of both sexes. It is well known that many children past the usual age of toilet-training suffer from nocturnal enuresis, and that the elderly are quite likely to develop bladder over-activity or urinary incontinence as they grow older. However, some studies have reported daily incontinence among as many as 17% of young, apparently healthy, women. Thus, it is clear that reliable and safe methods of treating bladder over-activity and urinary incontinence are seriously needed.
Bladder over-activity and urinary incontinence can result from various neurological disorders; such as Parkinson's Disease, multiple sclerosis, spinal cord injury, stroke, and Alzheimer's Disease. Bladder over-activity can also result from various disorders localized to the lower urinary tract; such as prostatitis, prostatodynia, urethritis, interstitial cystitis, urinary tract infection, outlet obstruction, benign prostate hyperplasia, radiation therapy of the pelvic viscera, diabetes, or vulvodynia. Bladder over-activity can also be idiopathic.
Thus, it is clear that bladder over-activity and urinary incontinence are major disorders of today. It is believed to afflict approximately 12 million people in the United States alone, and to occur in from 15 to 30% of the population over the age of 60. Its treatment at present is quite unsatisfactory.
The therapies currently used for certain conditions listed above often do not resolve bladder over-activity and incontinence. For example, L-dopa treats the motor symptoms of Parkinson's disease, but can actually exacerbate bladder over-activity. Likewise, surgical removal of the prostate and the use of alpha adrenergic receptor antagonists can improve urine flow and decrease residual urine, but the symptoms of frequency, urgency, and nocturia often persist.
The mainstay therapy for treatment of bladder over-activity and incontinence are drugs that are muscarinic cholinergic receptor antagonists (“anticholinergics”) with varying degrees of calcium channel blocking activity. The only compounds prescribed in significant quantities are tolterodine and oxybutynin. Off-label use of tricyclic antidepressants, such as imipramine, which also exhibit significant anticholinergic properties is also practiced. These compounds work by blocking the excitatory effects of acetylcholine on the bladder smooth muscle, thus suppressing bladder contractions and reducing bladder over-activity. Unfortunately, these compounds not only suppress bladder over-activity, but they also suppress normal bladder activity, which results in increases in residual urine, i.e., the bladder does not empty completely and the remaining urine provides a medium for bacterial growth and subsequent urinary tract infections. A potential increase in residual volume is especially problematic for BPH patients who already have problems with residual urine due to obstruction of the urine outlet, i.e., the urethra. Thus, anticholinergic drugs are contraindicated for BPH patients. In addition, all of these “anticholinergics” cause undesirable side-effects typical of anticholinergic drugs such as dry mouth, constipation, etc., and the efficacy of anticholinergic compounds is only partial.
Currently, there are no medicines indicated for the treatment of stress urinary incontinence. Off-label use of sympathomimetics, such as psuedoephidrine, is practiced, but the efficacy is questionable. The only therapies currently recognized by physicians are behavioral modification, pelvic floor exercises, and surgery.
Over the last several years, various studies have implicated the neurotransmitter serotonin (5-hydroxytryptamine, 5HT) in control of lower urinary tract function. 5HT terminals and various receptor subtypes are intimately associated with spinal cord areas that contain afferent and efferent components of lower urinary tract neural control centers (Besson and Chaouch, Pain Headache, 9, 64-100 (1987); Y. Hosoya, et al., Exp. Brain Res., 86, 224-228, (1991); M. Kojima, et al., Cell Tissue Res., 229, 23-36 (1983); N. Rajaofetra, J. Comp. Neurol., 318, 1-17 (1992); K. B. Thor, et al., Neuroscience, 55, 235-252 (1993)). Pharmacological and physiological studies have indicated that the prevailing effects of 5HT receptor activation on the urinary bladder are inhibitory. (M. J. Epsey, et al., Eur., J. Pharmacol., 221, 167-170 (1992); Fakuda and Koga, Exp. Brain Res., 83,303-316 (1991); McMahon and Spillane, Brain Res., 234, 237-249 (1982); Steers and deGroat, Am. J. Physiol., R1441-1449 (1989); K. B. Thor, et al., Brain Res. Dev. Brain Res., 54, 35-42 (1990); Thor and Katofiasc, J. Pharmacol. Expt. Ther., 274, 1014-1024 (1996); and Thor et al., 1998).
It has been recognized that there are multiple types of 5-HT receptors. These receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5HT6 and 5-HT7. The most heterogeneous of these classes appears to be 5-HT1, subclassified as: 5-HT1A, 5-HT1B, and 5-HT1D (Hamon et al., Neuropsychopharmacol., 3(5/6), 349-360 (1990)) and 5-HT1E (Leonhardt et al., J. Neurochem., 53 (2), 465-471 (1989)). A human gene which expresses an additional 5-HT1 subclass, 5-HT1F was isolated by Kao and coworkers (Proc. Natl. Acad. Sci. USA, 90, 408-412 (1993)).
Thus, it is clear that there is an unmet medical need for pharmaceuticals that are effective for the treatment of bladder over-activity and urinary incontinence, and free from undesired side effects. The present invention provides such pharmaceuticals.